Scientists have long desired to more particularly understand the nature of inflammation of an immune response particularly in a diseased state clinically triggered by a virus or microbe. An understanding of virally or microbially infected cell behavior leading to a clinical diagnosis and treatment regime is highly desired to treat living diseased animals having chronic destructive autoimmune or autoimmune like diseases. Such understanding is intrinsically linked to a desire by medical practitioners to alleviate at least one of (a) a symptom of an infection, (b) excessive immune response(s) due to autoimmunity and (c) ineffective immune response caused by immunodeficiency. Practitioners desire to provide curative treatment to an underlying disease state of a distressed living human so that patient suffering is at least somewhat alleviated.
Type 1 interferons, proteins generated by natural interferon producing cells, are of particular significance in scientific studies and medicinal research. The level (i.e. concentration in mg/ml) of Type I interferons typically measured in serum recovered from blood is modulated in diseased state animals or in tissues of diseased state animals as compared to levels in healthy animals.
Natural interferon producing cells (IPC) were originally identified in human blood as a small subset of leukocytes that secrete high levels of interferon (IFN)-α and β when incubated in vitro with a variety of DNA and RNA viruses, including herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), Sendai virus and influenza virus1-5. More recently, it was shown that human and murine IPC also respond to single stranded oligodeoxynucleotides (ODN) containing deoxycytidylate-phosphate-deoxyguanylate (CpG) Motifs6-9, which mimic unmethylated CG dinucleotides found in microbial DNA10. Recognition of CpG ODN and certain viruses by IPC is mediated by Toll-like receptor 9 (TLR9)11. In addition to IFN-α and -β, IPC secrete IL-1212-14 and proinflammatory chemokines in response to viruses and CpG ODN15-17. Together, these cytokines and chemokines modulate the antigen presenting function of dendritic cells (DC)18, as well as recruiting and activating NK cells and T cells18. Furthermore, IPC themselves function as antigen presenting cells that expand memory T cells and induce Th1 differentiation17-20.
To interact with and activate NK cells, it is hypothesized that T cells and antigen presenting cells, IPC must migrate from the blood into lymph nodes during an immune response in vivo. Consistent with this hypothesis, human IPC are particularly abundant in inflamed lymph nodes of human individuals affected by chronic infections or autoimmune diseases, especially around high endothelial venules (HEVs)21,22. Moreover, IPC express homing molecules and chemokine receptors that can direct IPC migration from the blood into inflamed lymph nodes through HEVs5,15,23,24.
Although human IPC have been known for almost two decades, mouse IPC have been identified only recently. Furthermore, it has now been shown that IPC correspond with the enigmatic ‘plasmacytoid cells’ or ‘plasmacytoid’ identified in human lymph nodes during infections. These notions have brought IPC to the attention of immunologists for their role in innate immunity and in shaping T cell and B cell responses.
Demonstrating IPC recruitment and function in murine infection models has been difficult up to this time because multiple antibodies are required to distinguish IPC from other immune cells and very few can be recovered from lymphoid organs such as lymph nodes.
In mice, footpad immunization with HSV-1 induces a modest influx of IPC in draining lymph nodes25. To date, however, there is no experimental evidence that IPC accumulate in lymph nodes as a direct result of inflammation. Demonstrating IPC accumulation in mouse lymph nodes is difficult due to the low numbers of IPC and their complex phenotype (CD11c+, Ly-6C+, Gr-1+, B220+, CD11b−, CD8a+/−)13,23,26. A method of detecting IPC is highly desired.
Systemic lupus erythematosus (SLE) and SLE similar type diseases are of particular interest in the diagnosis and treatment of chronic devastating autoimmune diseases. Human patients with SLE would be expected to have an activated type I interferon system with ongoing Type I interferon synthesis (secretion).
Lupus is a particularly insidious destructive human autoimmune disease wherein the host's immune system attacks and destroys the human host's own body. Clinical features of lupus include inflammation, pain, fatigue and other possible long lasting host organ damage. It is highly desired to have an effective clinical medical treatment for this very painful debilitating and potentially fatal multisystem disease.
NIH Publication 02-5060 describes sarcoidosis as a disease that causes inflammation of the body's tissues. According to this NIH publication, inflammation of sarcoidosis can occur in almost any organ and always affects more than one organ.
Another devastating immune disease, arthritis, comprises more than one hundred different conditions. These conditions range from mild forms of tendinitis and bursitis to crippling systemic forms, such as rheumatoid arthritis. There are pain syndromes such as fibromyalgia, polymyalgia-rheumatica and other arthritis-related disorders, such as systemic lupus erythematosus “(SLE)”, that literally involve every part of the body. There are other forms of immune disease, such as gout and osteoarthritis (or osteoarthrosis).
Despite notable advances in understanding of Type I interferon secreting cells in living animals, it is still highly desired to identify and prepare antibody recognizing mice Type I interferon secreting cells and to have an effective murine living animal model(s) for determining the role played by IPC in an autoimmune inflammation state and for evaluating the efficiency of treatment of autoimmune disease state in murines with potentially therapeutic drug candidate(s).
While many scientific investigators have intensively investigated cellular and molecular mechanisms involved in the inflammation process and biometric aspects of such systems, particularly those involving SLE, therapeutic assessment, diagnostic and treatment regimes are still highly desired to be clearly determined as autoimmune diseased patients continue to suffer from painful afflictions.
Murine models of diseases, including viral, bacterial, cancerous and autoimmune, often mimic human diseases. Learning the role of IPC or type I interferons in these murine models will lend insight into the human disease counterpart.